DESCRIPTION (Investigator's abstract): Huntington's disease (HD) is a dominant inherited neurodegenerative disorder that affects 1 in 10,000 in the U.S. Knowledge of the HD mutation, a CAG expansion that extends a run of glutamines in huntingtin, has spurred elucidation of the HD pathogenic mechanism and related polyglutamine disorders. Mutant huntingtin's HD pathogenic-trigger comprises two components: a novel toxicity property of polyglutamine conferred on the amino terminus and another intrinsic feature of the 350 kDa protein that renders striatal neurons especially vulnerable. By inserting HD CAG repeats into the mouse's HD gene (Hdh), we have uncovered abnormal conformational properties of full-length mutant huntingtin that precede truncated-aggregate and neuronal atrophy. The striatal neuron specificity, dominance and glutamine progressively implicate these events early in the human disease. We have demonstrated by Hdh inactivation and studies in striatal cells that huntingtin displays alternate conformations (consistent with distinct complexes) that associate with different sets of nuclear RNA and cytoplasmic membrane organelles that require its function. We have demonstrated regulation of huntingtin levels that implicates it in a diversity of physiologic adoptions to altered cellular homeostasis. In the renewal period, we aim to pursue the delineation of both components of HD pathogenesis. To investigate the specificity element, we will more precisely define huntingtin's normal function, placing it within the RNAprotein energy pathway and delineating regulatory features important to the metabolism of striatal neurons. To define the polyglutamine component, we will assess modifications and interactions unique to mutant huntingtin, test factors that modify its abnormal behaviors and assess the contribution of physiologic regulation. Our long-term goal continues to be a detailed understanding of the initial steps of the HD pathogenic cascade in order to be able to target specific processes for the development of effective therapies for this tragic disorder.